David Van Heel - Human Knockouts

David Van Heel, Barts and the London

Kat - Although Eamonn and his team have found many genetic changes linked to disease, it’s not always that straightforward. A Bradford lad himself, David Van Heel is now Professor of Genetics at Barts and the London’s Blizard Institute. He’s been studying the Born in Bradford cohort to search for so-called ‘human knockouts’. More commonly associated with laboratory genetic engineering techniques involving mice or fruit flies, knockouts are organisms lacking both copies of a particular gene - the one from mum and the one from dad. And rather than being created in a lab, human knockouts are naturally-occurring, as he explained to me.

David - Everybody has some knockout genes. Normally, we have about a hundred or so genes where one copy doesn’t work and we thought that in the Bradford population, we would find people where two copies of the gene didn’t work for reasons I’ll tell you, and that that will be very interesting. Indeed, it’s turn out so there are actually healthy people who are absolutely fine with genes that don’t work and that actually tells us a lot about human biology.

Kat - Why is this population particularly interesting to try and find examples of these people who’ve got two faulty copies of particular genes?

David - So, I don’t like the word ‘faulty’ first of all. I like the word ‘different’. We all have lots of gene variation. Faulty implies that something might go wrong where it’s actually what we’ve been seeing is that we have been finding genes that are knocked out. So, you don’t have the protein but your health is unaffected. So, why it’s interesting in some south Asian populations, there's a higher rate of close related ancestors. So for example, people of Pakistani heritage in Bradford there's about 20 per cent, 30 per cent rate of people marrying their first cousins and children who are offspring of such a marriage will inherit two copies in some cases of a gene from the same ancestor.

Going back to the knockout study, we have done something called exome sequencing of 3,000 people from the Born in Bradford study. That’s where we’ve looked at all the protein coding genes in the genome in all those people and we’ve said actually, can we predict any of those genes might not work, where both copies don’t work. We’ve been finding that in those 3,000 people, there are about a thousand people with double gene knockouts. We’ve looked at their health records - they're mothers in the Born in Bradford cohort - and these people don’t appear to suffer any ill health. In terms of medicines or how often you see a doctor, but we do find some very interesting genes which are switched off.So for example, there are a couple of genes involved in hearing where children being described with variants in those genes which cause genetic hearing loss. But we’ve found adults with variants in those genes where the genes don’t work whose hearing is perfectly fine. Indeed, some of them have had audiometry which is a proper hearing test and that’s completely normal. So, what that’s saying is that actually, for some genetic variants which are thought to cause a genetic disease, actually, when you look in healthy populations, you can find those genetic variants.

And that suggests that the risk is actually considerably less than might have been thought and has implications for the advance of genome sequencing - there's now a lot of companies offering genome sequencing. You can go out and buy your own genome sequence and there's a lot of ethical discussion about feedback of results. But what we have shown is that even for the genetic changes which might have the most obvious effect on a protein in many cases whilst they might alter biological pathways, they don’t affect health.

Kat - It almost sounds contradictory to what many people might have the idea of genetics that a difference or a change in one gene. If you get two versions of it, that causes a disease, the sort of idea of Mendel’s one gene-one disease. What your finding suggests that people can be walking around with these differences that should cause them a problem, but don’t. So, what's going on? Is something else compensating? What do we know?

David - So, I think you're right. Something else is compensating. The variants we find definitely change the protein but don’t give the person the condition that might be expected from studies of big multiply-affected families. Actually, I think it just compensation that there are another 19,000 genes in the genome other than the one we’re looking at and the variation in those can compensate. What we’ve done by studying mothers who came to the antenatal clinic is actually pick healthy people so there's what's known as an ascertainment bias. It’s the exact opposite of what people studying rare diseases have done. They’ve picked people with rare diseases and picked a very severe end of the spectrum. We’ve picked a very no-disease end of the spectrum and perhaps it’s not surprising that we’re finding somewhat different and lower risks.

Kat - Where next? How do we start to unpick and understand what's going on and then use that information for health benefits?

David - So, there's a whole variety of things we can do. We’re setting up this big study, Genes and Health, taking adults from the population. So, we’re not specifically going for healthy, but we’re not looking for people with rare and severe diseases. And so, there's quite a lot of other things like drug response. We’re looking at people with diabetes, particularly in south Asian populations with very high rates of diabetes and outcomes from that. Although I've been saying that the risks for some of these genetic variants are lower, they're not zero. So for example, in the Bradford population, we have found 40 people who have knockouts in genes which should cause a recessive genetic disease and looking back at their health records, we found about 20 per cent of those people do actually have the condition that the Mendelian databases suggest. But 80 per cent that we think that’s an example of this reduced penetrance of genetic conditions.

Kat - David Van Heel, from Barts and the London, and thanks to Laura Lamming, the Born in Bradford team and the National Media Museum for allowing me access to their meeting.

There are apparently a whole bunch of other useful Caucasian mutations, including a tolerance of alcohol (which permitted the growth of cities that would otherwise have been unsustainably insanitary, and exploration by long sea voyages) and the ability to digest cheese (thus providing storeable protein in northern Europe).

Having eradicated most communicable diseases, and developed agriculture to a state of continuing surplus, it is arguable that western man has no environmental stresses that will lead to further evolution.
alancalverd, Mon, 14th Sep 2015

Is that perspicacious enough?

Or do you want to wait for the next pandemic to see who has evolved and who has not -as was the case with the plague?
Franklin_Uhuru, Mon, 14th Sep 2015

Evolution hitherto has been a lottery, and many species seem to have drawn losing numbers. So let's suppose that we can design and manufacture homo futuralis to do just one thing better than anyone around at present.

What characteristic would you choose to enhance?

Would the new species (a) be able to reproduce at will, or must they (b) be made to order (like mules and sterile GM crops)

If (a), would it compete with homo sapiens for resources?

If (b), how many would you make? And for what purpose? In a mechanised world, we don't need any more bodies, so would they be pets, perhaps? They will need feeding, so any significant number will compete with the poorest humans for food.

It would be nice, for instance, if hom fut was not susceptible to breast cancer. This clearly makes economic sense as well as being emotionally desirable. If (a) they obviously won't want to interbreed with us as that will risk losing their genetic superiority. So will they eventually decide to discontinue breast cancer services for the remaining hom saps?

Whether (a) or (b), we would indeed be a remarkable species - the first ever to vote for its own extinction.
alancalverd, Wed, 16th Sep 2015

Only the most chauvinistic simpleton would imagine that we are the pinnacle - the end product of evolution. We are going to become extinct. We either evolve into the next version of humanity or we die off. Exuent Omnes. Pax vobiscum.

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